7-73340685-C-A

Position:

• chr7-73340685-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003602.5(FKBP6):​c.636C>A​(p.His212Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: FKBP6 NM_003602.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.779

Genes affected

FKBP6 (HGNC:3722): (FKBP prolyl isomerase family member 6 (inactive)) The protein encoded by this gene is a cis-trans peptidyl-prolyl isomerase that may function in immunoregulation and basic cellular processes involving protein folding and trafficking. This gene is located in a chromosomal region that is deleted in Williams-Beuren syndrome. Defects in this gene may cause male infertility. There are multiple pseudogenes for this gene located nearby on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09586322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP6	NM_003602.5	c.636C>A	p.His212Gln	missense_variant	6/9	ENST00000252037.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP6	ENST00000252037.5	c.636C>A	p.His212Gln	missense_variant	6/9	1	NM_003602.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.636C>A (p.H212Q) alteration is located in exon 6 (coding exon 6) of the FKBP6 gene. This alteration results from a C to A substitution at nucleotide position 636, causing the histidine (H) at amino acid position 212 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.035	.;.;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	.;.;.;L
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.36	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.11	B;.;.;B
Vest4		0.21
MutPred		0.26		.;.;.;Gain of relative solvent accessibility (P = 0.0999);
MVP		0.78
MPC		0.31
ClinPred		0.094	T
GERP RS		2.9
Varity_R		0.066
gMVP		0.051

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1419940250; hg19: chr7-72754687;